WD-40 proteins contain a loosely conserved repeat of approximately 40 amino acids separated by a Trp-Asp dipeptide sequence which may recur several times within the polypeptide. The conserved core of this sequence, which usually ends with the amino acids Trp-Asp (WD), was first identified in the .beta.-subunit of the heterotrimeric GTP-binding protein, transducin. Several dozen WD-40 proteins have since been identified; none are enzymes, and all seem to have regulatory functions (Neer, E. J. et al. (1994) Nature 371:297-300).
Many of the WD-40 proteins are homologs of .beta.-transducin and function in signal transduction pathways within the cytoplasm. These proteins may participate in complex formation, sometimes interacting with other G protein subunits through the WD-40 region. The .beta. subunit of G-proteins enhances binding of the G.sub..alpha. subunit to receptors and assists in the assembly of the G-protein:receptor complex. The G.sub..beta..gamma. subunit binds to and brings the .beta.-adrenergic receptor kinase, .beta.-ARK, to the receptor (Touhara, K. et al. (1994) J. Biol. Chem. 269: 10217-10220).
A number of WD repeat proteins have been identified that are localized to the nucleus and function in the repression of transcription. These include Tup1, Hir1, and Met30in S. cerevisiae; SCON2 in Neurospora crassa; extra sex combs and Groucho in Drosophila; COP1 in Arabidopsis thaliana; and HIRA and the family of TLE proteins in humans. These WD-40 proteins turn off a wide variety of genes, including those involved in segmentation, sex determination, and neurogenesis (controlled by Groucho) and those involved in photomorphogenesis (controlled by COP1). Of these WD-40 repressor proteins, Tup1 is the most fully characterized.
Tup1 along with another protein, Ssn6, is required for the repression of at least five sets of genes in Drosophila. These include the glucose-repressed genes, genes regulated by the presence of oxygen, the .alpha.-specific and haploid-specific genes, and a set of genes induced by DNA damage. A deletion of SSN6 or TUP1 results in the constitutive expression of all of these genes sets. In Xenopus laevis, a gene (gene 16) has been identified that is specifically up-regulated in the thyroid hormone-induced tissue remodeling that occurs during tail resorbtion. In C. elegans, gene coding for a WD-40 protein was recently found on chromosome III (Michael, J. R. et al. (1997) J. Biol. Chem. 272: 11193-11197; Brown, D. B. et al. (1996) Proc. Nati. Acad. Sci. 93: 1924-1929: and Wilson, R. et al. (1994) Nature 368: 32-38).
In Drosophila Groucho is part of a complex network of transcriptional regulatory proteins. These include the basic helix-loop-helix transcription factors that are involved in cell determination, partners that lack a basic domain and act as negative regulators, the Hairy-related proteins, which also act as negative regulators, and Groucho, which is required for repression of Hairy-related proteins. The human homologue of Groucho, TLE, is found in cells progressing towards terminal differentiation. TLE levels are elevated in cells resulting from incorrect or incomplete maturation events, such as metaplastic or neoplastic events. TLE1, TLE2, and TLE3 are coexpressed in a number of epithelial tissues and their expression is elevated in cervical squamous metaplasias and carcinomas. Additionally, another WD-40 protein, HIRA, has been implicated in the human developmental disease, DiGeorge syndrome (Liu, Y. et al. (1996) Genomics 31: 58-64; Halford, S. et al. (1993) Hum. Molec. Genet. 2: 2099-2107).
The discovery of two new WD-40 proteins and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer and developmental disorders.